The overall objective of this grant is to understand the role of indoor allergens in asthma. The importance of this study comes from the extraordinary prevalence of the disease, i.e. -8 percent of the population, and the very large numbers of patients who require treatment for acute asthma, i.e. more than 1 million cases per year. Central to these studies is the view that the immune response in susceptible children [which includes IgE antibodies (ab), IgG ab, IgG4 ab and Th2 cells] is dependent on exposure. The proposed studies involve epidemiology, techniques for measuring exposure, detailed evaluation of the immune response, and studies of the acute episodes. There are two contrasting views about the nature of the immune response in non-allergic individuals: (1) that they are non-responders (immune ignorance); or (2) that they have made an alternative form of immune response. During the last two years it has become clear that the presence of a cat in the home is associated with a decreased risk of asthma and that high exposure to cat allergen can induce a different immune response that includes IgG and IgG4 antibodies, but not IgE ab. This modified Th2 response provides an opportunity to investigate: the dose response relationship between allergen exposure and the risk of asthma; the nature of the immune response to allergens in allergic and non-allergic individuals; and the aspects of the immune response that create the risk of asthma. These results suggest that the dose response relationship between exposure and sensitization is bell-shaped for cat allergen and linear for dust mite allergen. The experiments proposed will focus on: (I) the analysis of the relationship between exposure, serum antibody responses to indoor allergens, and the risk of asthma in prospective studies on three cohorts of children; (II) detailed investigation of the response of circulating T cells to mite and cat allergens using natural allergens, recombinant proteins and overlapping peptides spanning each of the molecules. These studies will evaluate differences in T cell epitope recognition, cytokine responses in vitro and cell surface phenotype of T cells from subjects with different exposure and different immune responses. (III) Investigation of the relationship between allergic responses and acute episodes of asthma using three approaches: following patients prospectively; experimental rhinovirus challenge of allergic and non-allergic individuals; as well as investigating patients presenting with asthma to the Emergency Room or hospital. The studies proposed have important implications for asthma treatment using allergen avoidance, or for novel strategies for allergen specific immunotherapy.